Novel 11beta,18-epoxy steroids

ABSTRACT

NOVEL 11B,18-EPOXY-$4.9-ESTRADIENES OF THE FORMULA   3-(O=),11,18-(-O-),17-R,17-(R&#39;&#39;-O-)ESTRA-4,9-DIENE   WHEREIN R IS SELECTED FROM THE GROUPS CONSISTING OF HYDROGEN AND ETHYNYL AND R&#39;&#39; IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ACYL OF AN ORGANIC CARBOXYLIC ACID OF 1 TO 18 CARBON ATOMS, LOWER ALIPHATIC, ARALYALIPHATIC AND HETEROCYCLIC WHICH HAVE ANIT-ANDROGENIC ACTIVITY, THEIR PREPARATION AND INTERMEDIATES THEREFROM.

United States Patent C 3,699,100 NOVEL 11 3,18-EPOXY STEROIDS Lucien Nedelec, Clichy-sons-Bois, and Jean-Claude Gasc, Bondy, France, assignors to Roussel-UCLAF, Paris, France No Drawing. Filed Feb. 3, 1971, Ser. No. 112,386 Claims priority, applic7a,t(i] ;r1lgrance, Feb. 11, 1970,

Int. Cl. C07c 173/00 US. Cl. 260-23955 R 7 Claims ABSTRACT OF THE DISCLOSURE Novel l1p,l8-epoxy-A -estradienes of the formula o cH,

wherein R is selected from the group consisting of hydrogen and ethynyl and R is selected from the group consisting of hydrogen, acyl of an organic carboxylic acid of 1 to 18 carbon atoms, lower aliphatic, arylaliphatic and heterocyclic which have anti-androgenic activity, their preparation and intermediates therefrom.

OBJECTS OF THE INVENTION wherein R is selected from the group consisting of hydrogen and ethynyl and R is selected from the group consisting of hydrogen, acyl of an organic carboxylic acid of .1 to 18 carbon atoms, lower aliphatic, arylaliphatic and heterocylic. Particularly preferred are 11,8,18-epoxy-17aethynyl A estradiene-17/3-ol-3-one and 1118,18-epoxyl7fl-acetoxy-A -estradiene-3-one.

Examples of suitable organic acids of l to 18 carbon atoms may be derived from an aliphatic, aromatic, cycloaliphatic or heterocyclic carboxylic acid. Examples of suitable acids are alkanoic acids, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trirnethyl acetic acid, caproic acid, fi-trimethyl propionic acid, heptanoic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid and stearic acid; alkenoic acids, such as undecylenic acid and oleic acid; cycloalkyl carboxylic acids, such as cyclopentyl carboxylic acid, cyclopropyl carboxylic acid, cyclobutyl carboxylic acid and cyclohexyl carboxylic acid; cycloalkyl alkanoic acids, such as cyclopentyl acetic acid, cyclohexyl acetic acid, cycle pentyl propionic acid and cyclohexyl propionic acid; arylalkanoic acids, such as phenyl acetic acid and phenyl propionic acid; aryl carboxylic acids, such as benzoic acid and 2,4-dinitrobenzoic acid; phenoxy alkanoic acids, such as phenoxy acetic acid, p-chlorphenoxy acetic acid, 2,4- dichlorophenoxy acetic acid, 4-ter-buty1phenoxy acetic acid, 3-phenoxy propionic acid and 4-phenoxy butyric acid; heterocyclic carboxylic acids, such as furane-2-carboxylic acid, S-tertbutylfurane-Z-carboxylic acid, S-bromofurane-Z-carboxylic acid and nicotinic acids; fi ketoalkanoic acids, such as acetylacetic acid, propionylacetic acid and butyrylacetic acid.

Examples of suitable alcohols for forming the ethers of Formula I are lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, the butanols, the pentanols, allyl alcohol, etc.; arylaliphatic alcohols, particularly phenyl lower alkanols such as benzyl alcohol and heterocyclic alcohols such as tetrahydropyranol.

The novel process for the preparation of the compound of Formula I wherein R is hydrogen and R is ethynyl comprises reacting 3 methoxy-A -estratriene-l1p, 17 B-diol with acetic acid anhydride to selectively acetylate the 17 position, reacting the resulting 3-methoxy-17flacetoxy-A -estratriene-1lB-ol with nitrous acid to form S-methoxy 11,3 nitrosoxy 17B acetoxy-A estratriene, irradiating the latter in the presence of iodine to form 3-methoxy-l7B-acetoxy-18-iodo-A -estratriene-llfl-ol, reacting the latter with a strong base to form 3 methoxy 115,18 epoxy A -estratriene--01, reducing the latter by the Birch reaction with lithium in liquid ammonia in the presence of an alcohol to form 3-methoxy-11p,18-epoxy-A -estradiene-l7fl-ol, reacting the latter with a ketalization agent in an acid media to form the S-ketal of 11B,l8-epoxy-A -estrene-1718-01- 3-one, oxidizing the latter by the Oppenauer reaction with aluminum lower alcoholate in the presence of a hydrogen acceptor to form the 3 ketal of 11B,18-epoxy-A estrene-3,17-dione, reacting the latter with an alkali metal acetylide and then hydrolyzing the product with a weak acid to obtain 1lfl,l8-epoxy-l7a-ethynyl-A -estrene- 17B-ol-3-one and reacting the latter with bromine in the presence of an organic tertiary base to form 115,18- epoxy-17a-ethynyl-A -estradiene-l7fl-ol-3-one which may be esterified or etherified in the 17-position by classical methods.

The selective acetylation of the 17-position of 3-methoxy-A -estratriene-l113,17fl-diol is realized by reaction with acetic acid anhydride in a pyridine medium for 15 hours at 0 C. The nitroso derivative is preferably formed by reaction with an alkali metal nitrite in a mixture of acetic acid and acetic acid anhydride.

The photolysis of nitrous esters of steroids to introduce a bromine or iodine atom in the 18-position is described by Akhtar et al. [J.A.C.S., vol. 87 (1965), p. 4601]. The photolysis step is effected in the process of the invention in the presence of iodine while circulating a toluene solution of the nitrosoxy compound in a Pyrex glass serpentine under the light of a 250 watt Hanovia mercury vapor lamp while under an inert atmosphere. The raw mixture of the irradiation is preferably subjected to chromatography to recover 3-methoxy-l7B-acetoxy-l8-iodo-A estratriene-l 15-01.

The formation of the llfi-l8-epoxy group is effected by reacting 3-methoxy-l7fi-acetoxy-18-iodo-A -estratriene-llB-ol with a strong base such as an alkali metal methylate, ethylate or tert.-butylate, preferably in a mixture of lower alkanols, tetrahydrofuran and hexamethyl phosphortriamide. The reduction of the resulting product is preferably effected by the classical Birch method with lithium in liquid ammonia in the presence of an alcoholsuch as ethanol.

The formation of the 3-ketal is preferably effected by reacting 3-methoxy-115,18-epoxy-A -estradiene-175-01 with a. 2,2-diallcyldioxolane in the presence of an acid such as sulfuric acid or p-toluene sulfonic acid and 2- methyl-2-ethyl-dioxolane is preferred.

With the 3-ketone group protected by the ketal group, 175-o1 group of l15,18-epoxy-A -estrene-175-0l-3-one can be oxidized by the Oppenauer method by reaction with an aluminum lower alcoholate or aluminum phenolate in the presence of a hydrogen acceptor such as lower ketones or aldehydes like cyclohexanone, benzoquinone, chloranil or anisaldehyde. The solvent is preferably an aromatic hydrocarbon like benzene, toluene or xylene.

The 17a-ethynyl substituent is introduced by reacting the S-ketal of 1l5,18epoxy-A -estrene-3,l7-dione with an alkali metal acetylide which can be'formed by reacting acetylene with an alkali-metal alcoholate such as potassium tert.-amylate or tert.-butylate or withan alkali metal amide. The reaction is preferably effected in a ether such as isopropyl ether or tetrahydrofuran.

The hydrolysis of the 3-ketal group of 115,18-epoxy- 17a-ethynyl-A estrene-l75-ol-3-one is preferably effected with a weak acid such as acetic acid or citric acid, most preferably in an aqueous medium in the presence of excess acid or a solvent such as methanol, ethanol or benzene or a mixture of said solvents. The formation of the 3-oxo-A system from 3-oxo-A is effected with a dehydrogenation agent, preferably bromine in the presence of an organic tertiary base such as pyridine. The reaction is effected preferably in a lower alkanol such as methanol, ethanol or isopropanol.

The esterification of the 175-01 group may be effected by reaction with an acylating derivative of the desired acid such as the acid chloride or acid anhydride preferably in the presence of a tertiary amine. The etherification of the 175-01 group may be effected .by reaction with a halide of the desired hydrocarbon on an alkali metal derivative of the 175-01.

The 115,18-epoxy steriods of Formula I where R and R are both hydrogen are prepared by reacting 3-methoxyl15,18-epoxy-A -estradiene-l75-ol, prepared as discussed supra, With a Weak acid to form 115,18-epoxy- A -est-.rene-175-ol-3-one and reacting the latter with bromine in the presence of an organic tertiary base to form 1l5,1 8repoxy-A -estradiene-l75-ol-3-one which may be esterifiecl or etherified-by classical methods.

The weak acid to whose action the enol ether is subjected is preferably acetic acid and the reaction with bromine is preferably efiected as discussed above.

In a variation of the process of the invention, 3-methoxy-l15-nitrosoxy-175-acetoxy-A estratriene is subjected to photolysis to form 3-methoxy-175-acetoxyl8-hydroxyimino-A -estratriene-l15-01, reacting the latter with an acid agent to form 3-methoxy-1 15,18-ep0xy- A -estratriene-175,18-diol, reacting the latter with a reducing agent to obtain 3-methoxy-A -estratriene- 115,175,18-triol, reacting the latter with acid agent to obtain 3 methoxy-l15,18-epoxy-A -estratriene-l75- 01 which may be treated as in the above synthesis.

- The photolysis is effected in a manner analogous to that of Akhtar et al. by circulating a toluene solution of the nitrous ester through a Pyrex glass serpentine while irradiating with a 250 w. Hanovia lamp. Preferably, a tertiary organic base such as triethylamine is present during the photolysis.

The acid agent used to change the 18-hydr0xyimino compound into the corresponding 115,18-epoxy comhydrochloric acid in a mixture of acetone and acetic acid is used.

The reduction step is preferably effected with lithium aluminum hydride in an ether solvent such as isopropyl ether or tetrahydrofuran to form 3-methoxy-A estratriene-l15,175,18-tri01. The acid treatment of the latter is preferably done with p-toluene sulfonic acid in an organic solvent such as benzene, toluene or xylene.

The novel anti-androgenic compositions of the invention are comprised of an effective amount of an 115,18-epoxy steroid of Formula I and a major amount of a pharmaceutical carrier. The compositions may be in the form of injectable suspensions or solutions in ampoules or multiple dose fiacons or in the form of tablets, coated tablets, sublingual tablets, capsules, suppositories, pommades, creams or lotions, prepared in the usual manner. The individual dose is 10 to 500mg.

Because of their important anti-androgenic activity, the compositions of the invention are useful for the treatment of prostatic adenome, hyperandrogenia, acne or hirsutism. The compositions have the great advantage with respect to known anti-androgenic agents by manifesting a moderated progestomimetric activity and no antihypophysial activity.

The novel method of the invention of inducing antiandrogenic activity in warm-blooded animals comprises administering to warm-blooded animals an effective amount of an 115,18-epoxy-steroid of Formula I. The said steroid may be'administered orally, perlingually, transcutaneously, rectally or locally by topical application. The usual daily dose is l to 20 mg./kg. depending upon the method of administration.

In the following examples, there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE I Preparation of l15,18-epoxy-l7a-ethynyl-A estradiene-175-ol-3-one Step A: S-methoxy-175-acetoxy-A -estratriene-l15- ol.-23 g. of 3-methoxy-A -estratriene- 115,175-diol [described by Stein et al., Tetra. Letters, 1967, p. 3603] were dissolved in cc. of pyridine with stirring and after cooling the solution to -l0 to --15 C., 23 cc. of acetic anhydride were added thereto. The reaction mixture was allowed to stand overnight at 0 C. and then excess acetic anhydride was destroyed by the addition of a few cc. of water without exceeding 10 C. The mixture was stirred for 15 minutes and then sufiicient water was added to start crystallization and then 300 cc. of water were added. The mixture was vacuum filtered and the precipitate was washed with water and dried 1 hour in air. The precipitate was dissolved in 300 cc. of methylene chloride and the aqueous phase was decanted off. The organic phase was dried over magnesium sulfate and was passed through magnesiumsilicate and distilled to dryness. The residue was crystallized from isopropyl ether to obtain 14.37 g. (55% yield) of 3-methoxy-175-acet0xy-A estratriene-l15-ol. Concentration of the mother liquors gave another 5% yield of the product.

For analysis, the product was crystallized from isopropyl ether. The compound occurred in the form of colorless needles melting at C. and having a specific rotation [0c] =+-110i2 (c.=0.5% in chloroform). The product was soluble in alcohols, ether, acetone, benzene and chloroform and was insoluble in water.

Analysis.--C H O molecular weight=344.43. Calculated: C, 73.22%; H, 8.19%. Found: C, 73.5%; H, 8.2%. As far as is known, this compound is not described in the literature.

Step B: 3-methoxy-l15-nitrosoxy-l75-acetoxy-A estratriene.-A mixture of 1 g. of 3-methoxy-175-acetoxy- 13 -estratriene-115-01, l0 cc. of acetic acid, 2 cc. of

acetic anhydride and 0.5 g. of sodium nitrite was stirred for 40 minutes at room temperature and was then added to a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ether and the ether phases were washed with water, dried over sodium sulfate, filtered and distilled to dryness under reduced pressure to obtain 1.15 g. of 3-methoxy-1lfl-nitrosoxy-l7 8-acetoxy-A estratriene which was used as is for the next step. .97 g. of pure product were obtained by chromatography over silica gel and elution.

LR. spectrum (chloroform): Presence of ONO complex at 1657 and 1644 cm.-

U.V. spectrum (ethanol): Max. at 277-278 m e=2250; max. at 286 mu, e=2050. I

As far as is known, this compound is not described in the literature.

Step C: 3-methoxy-17B-acetoxy-18-iodo-A -estratriene-11fi-ol.-A solution of 14 g. of 3-methoxy-11finitrosoxy-17/3-acetoxy-A -estratriene in 750 cc. of toluene containing 4.8 g. of iodine was irradiated with a 250 w. Hanovia lamp for 36 hours at room temperature while bubbling nitrogen therethrough and the thus irradiated solution was washed with sodium hyposulfite solution and then with water. The solution was distilled to dryness under reduced pressure and the residue of 15 g. was taken up in 40 cc. of a 9:1 mixture of benzene and ethyl acetate. The'crystals were separated by vacuum filtration and the mother liquors were subjected to chromatography over silica H and elution with a 9:1 benzeneethyl acetate mixture. The first-fraction had 3.8 g. of 3-methoxy-17fi-acetoxy-18 iodo-A -estratriene-11B- ol and the crystalline residue was empasted with cc. of boiling isopropyl ether to obtain 2.34 g. of the said product in the form of cream crystals melting at 205- 210 C. The product was soluble in chloroform, slightly soluble in ethanol and insoluble in water and isopropyl ether.

Analysis.-C H I'O molecular weight=470.35. Calculated: I, 26.98%. Found: I, 26.9-27.1%.

RMN spectrum in deuterochloroform agreed with the said structure.

, (LR. spectrum (chloroform): Presence of 0:0v at 1736 cm.- (acetate function) and of OH at 3560 cm.- and;of1a band corresponding to an ether of phenol.

As far as is known, this compound is not described in the literature. 1

Step D: 3-methoxy-11p,18-epoxy-A -estratriene- 17.[.t-.ol.--10.3 g. of 3-methoxy- 17/3 acetoxy-18-iodo- A -estratriene-115-01 were suspended in a mixture of 103 cc. of methanol, 103 cc. of tetrahydrofuran and 20.6 cc. of hexamethyl phosphotriamide and after cooling the suspension to 10 C., 6.23 g. of sodium methylate were added thereto. The reaction mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere and then 800 cc. of a water-ice mixture was added thereto with continued stirring. The mixture was vacuum filteredand the precipitate was washed with water and dried under reduced pressure to obtain 5.92 g. of 3-methoxy 11 9,18 epoxy-A -estratriene-176-01 in the form of a colorless solid melting at 170 C. The product was soluble inchloroform. I

I.R. spectrum (chloroform): Presence of OH at 3600 cm.'- and of aromatic at 1609, 1577 and 1497 cm.-

, As far as is known, this compound is not described in the literature.

Step E: 3-methoxy 115,18 epoxy-A -estradiene- 17;3-ol.120 cc. of tetrahydrofuran and 4 cc. of ethanol were added to 120 cc. of ammonia cooled to -30 C. and 5190 g. of 3-methoxy- 11 8,18 epoxy-A -estratriene-l7B-ol were dissolved in the mixture. After cooling to -50 C., 1.66 g. of lithium were added to the solution'and the mixture was stirred for 40 minutes at this temperature. Excess lithium was destroyed by the addition of 30 cc. of ethanol at -50 C. and the ammonia was distilled ofi. The residue was added to 300 cc.

of ice water and was then added to a mixture of 'ice-' water and the mixture was allowed to stand for 30 minutes. The mixture was vacuum filtered and the precipitate was washed with water and dried under reduced pressure to obtain 5.40 g. of 3methoxy-llj3,l'8-epoxy- A -estradiene-175-01 in the form of a colorless solid melting at 177 C. after crystallization from a 9-1 mixture of isopropyl ether-methanol. The product was soluble in chloroform and ethanol and insoluble in water.

I.'R. spectrum (chloroform): Presence of C==C at 1698 and 1666 cm.-

As far as is known, this compound is not described in the literature.

Step F: 3-ethylenedioxy 11 8,18 epoxy-A -estrene- 17fi-ol.A mixture of 5.4 g. of 3-methoxy-11[3,18-epoxy- A -estradiene-l7B-ol, 108 cc. of methyl ethyl dioxolane, 2.12 cc. of glycol and 108 mg. of p-toluene sulfonic acid was stirred at room temperature for 15 hours and then the reaction mixture was neutralized by the addition of triethylamine. The mixture was added to water and extracted with methylene chloride. The combined organic phases were washed several times with water, were dried over sodium sulfate, was filtered and distilled to dryness under reduced pressure to obtain 7 g. of 3-ethylenedioxy-11B,18-epoxy-A -estrene-17B-ol which was purified by chromatography over silica with elution with a 1:1 mixture of chloroform and acetone containing 0.2% of trieth'ylamine to obtain a first crop of 3.85 g. of said product.

I.R. spectrum (chloroform): Presence of ketal; presence of OH at 3598 cmr As far as is known, this compound is not described in the literature.

Step G: 3-ethylenedioxy-l15,18-epoxy-A -estrene 17-one.-20 cc. of toluene were distilled off from a mixture 0f 3.8 g. of 3-ethylenedioxy-11,6,-18-epoxy-A estrene-l7fl-ol, 133 cc. of toluene and 38 cc. of cyclohexanone and then a solution of 2.28 g. of aluminum isopropylate in 114 cc. of toluene were added thereto in 20 minutes while distilling to maintain a constant volume. The mixture was refluxed for 10 minutes and 100 cc. of an aqueous 'solution containing 1 8 g. of sodium and potassium tartratewere added thereto. The solvents were entrained with steam and the mixture was cooled and extracted with methylene chloride. The methylene chloride phase was washed with water, dried over sodium sulfate, was filtered and distilled'to dryness under reduced pressure to obtain 3.8 g. of 3-ethylenedioxy-11B, 18-epoxy-A -estrene-17-one which was used as is for the next step.

For analysis the product was purified by chromatography over silica, with elution with a 6:4 mixture of chloroform and acetone, and empasted in isopropyl ether. The product obtained was melted at 177 C.

(IJR. spectrum (chloroform): Presence of (i=0 at 17 at 1725 cmr presence of ketal; absence of OH.

As far as is known, this compound is not describedin the literature. I I

Step H: 3-ethylenedioxy 115,18 epoxy-17 a-ethylnyl- A -estrene-17Bol.A solution of 4 g. of potassium tert.-butylate in cc. of tetrahydrofuran was cooled to 5 C. and a current of acetylene was passed therethrough for 40 minutes. 3.8 g. of the product of step G in solution in 38 cc. of tetrahydrofuran were added thereto and the mixture was stirred for 40 minutes at room temperature. cc. of iced aqueous sodium chloride solution were added and the mixture was extracted with methylene chloride. The organic phase was washed with water and was dried over sodium sulfate, was filtered and dis stilled to dryness under reduced pressure to obtain 3.72 g. of raw 17a-ethynyl product. The raw product was purified by chromatography over silica and elution with a 7-3 mixture of chloroform and acetone containing 0.2% triethylamine to obtain 2.76 g. of 3-ethylenedioxy-11 8,18-

7 epoxy-17a-ethynyl-A -estrene-17fi-ol melting at 242- 244 C. 410 mg. of the product was empasted to obtain 345 mg. of the product in the form of cream crystals melting at 244 C. and soluble in chloroform and insoluble in water.

IR spectrum (chloroform): Presence of OH at 3580 cm.- of CECH at 3287 cmrf and of ketal.

As far as is known, this compound is not described in the literature.

Step I: 11fl,18-epoxy-17u-ethynyl A500) estrene-17flethynyl-A -estrene-175-01 dissolved in 96 cc. of acetic acid containing 25% water was stirred for six hours at room temperature and the reaction mixture was added to icedwater. The mixture was vacuum filtered and the precipitate was washed with water. and dried under reduced pressure in an oven to obtain 2.10 g. of 1119,18- epoxy-17a-ethynyl-A -estrene-17 3-ol-3-o11e in the form of cream crystals melting at 258 C.

LR. spectrum (chloroform): Presence of OH at 3588 cmr of C-=-CI-I at 3300 cm.- and of C=O at 1752, 1720 and 1710 cm.-

As far as is known, this compound is not described in'the literature.

: Step J: 11 3,18-epoxy-17a-ethynyl-A -estnadiene-175-01- 3-one.--A solution of 2.09 g. 11B,18-epoxy-17a-ethynyl- A -estrene 17fl-ol 3-one in 21 cc. of pyridine cooled to C. was admixed with 3.47 cc. of a methanolic solution of 32.4 g. of bromine per liter and the mixture was stirred for 16 hours at room temperature. The mixture was poured into water, vacuum filtered'and the precipitate was washed with water to obtain 1.39 g. of 11p, 1 8-epoxy-17a-ethynyl-A -estradiene-17p-ol-3-one melting at 280 C.

For analysis, the product was crystallized from a 1:1 pyridine-methanol mixture to obtain. cream crystals melting at 280.5 C. and having a specific rotation [oz] 149 C..-L-2 (c.'=1% in pyridine). The product was insoluble in water and in most of the usual organic solvents.

Analysis.-C H O molecular weight=310.38. Cal-v culated (percent): C, 77.38; H, 7.14. Found (percent): C, 77.2;.H, 7.0.

LR. spectrum (Nujol): Presence of OH and ::CH at 3295 and 3257 cm. presence of CECH at 2175 cm.- and of conjugated carbonyl of-the dienone type at 1660, 1583.and 1559 cm.-

far as is known, this compound is not described in the literature.

EXAMPLE H Preparation of 11/3,18 epoxy-17B-acetoxy- A -estradiene-3-one Step A: 1113,18-epoxy-A -estrene-17fl-ol-3-one.730 mg. of 3-methoxy-115,18-epoxy-A -estradiene-UB-ol dissolved in 11 cc. of acetic acid containing 25% water was stirred for 2% hours at room temperature and the reaction mixture was poured into ice water. The mixture was extracted with methylene chloride and the organic phases were washed with a saturated aqueous sodium bicarbonate solution, then water, dried over sodium sulfate, filtered and distilled to dryness under reduced pressure. The residue was empasted with 5 cc. of ether and was iced. The mixture was vacuum filtered and the precipitate was dried to obtain 51 8 mg. of 115,18-epoxy- A -estrene-17fi-ol-3-one in the form of a colorless solid melting at 116 C. The product was soluble in chloroform and insoluble in water.

IR. spectrum (chloroform): Presence of OH at 3600 cm.- of ketone at 1710-1713 cm." and of cyclic CO-C.

As far as is known, this compound is not described in the literature.

Step B: 115,18-epoxy-A -estradiene-l7fi-ol-3-one.-1.6 cc. of a methanolic solution of bromine titrating 19 g.

per 100 cc. were added to a solution of 518 mg. of 115, 18-epoxy-A -estrene-1713-01-3-one in 5.1 8 cc. of pyridine cooled to 0 C. and the mixture was stirred for 16 hours at room temperature. 10 cc. of ice water were added thereto and the mixture was extracted with methylene chloride. The organic extracts were washed with N hydrochloric acid, then with water and was dried over sodium sulfate, filtered and distilled to dryness under reduced pressure. 100 mg. of the residue were dissolved in a boiling 9:1 isopropyl ether-ethyl acetate mixture and the solution was iced and vacuum filtered. The precipitate was dried to obtain 70 mg. of 11p,18-epoxy-A estradiene-17/3 ol-3-one in the form of cream crystals melting at 174 C. The crystals were soluble in ethanol and chloroform and insoluble in water.

LR. spectrum (chloroform): Presence of dienone at 1661, 1626 and 1590 cm." and of OH at 3600 cm.-

U.V. spectrum (ethanol):

As far as is known, this compound is not described in I the literature.

Step C: 115,18-epoxy-17p1-acetoxy-A 1 estradiene 3- one.--A mixture of 498 mg. of 11B,l8-epoxy-A -estradiene-l7 8-ol-3-one, 3 cc. of pyridine and 1.5 cc. of acetic acid anhydride was stirred at room temperature for 2% hours and then was added to 15 cc. of ice water. The mixture was extracted with methylene chloride and the organic phase was washed with N hydrochloric acid, then with water. The said phase was then dried over sodium sulfate, was filtered and distilled to dryness under reduced pressure. The residue was purified !by chromatography over silica and elution with a 9:1 mixture of chloroform and ace.- tone. The product was crystallized from hot and cold isopropyl ether to obtain 252 mg. of 11/3,18-epoxy-17j8-acetoxy-A -estradiene-3-one in the form of colorless crystals melting at 116.5 C. and having a specific rotation (c.=0.6% in ethanol). The product was soluble in ethanol and chloroform and insoluble in water. j

Analysis.C H O molecular weight=328.39. Calculated: C, 73.14%; H, 7.37%. Found: C, 73.2%; H, 7.3%.

LR. spectrum (chloroform): Absence of OH andv presence of C=O dienone at 1661 cmrof --C=C at 1629 and 1592 cm.- and of C=O (acetate) at 1738 emf- U.V. spectrum (ethanol):

Max. at 213-214 mu Eiz =192 Inflex towards 231-232 my. Eli E 149 e=21,700 Max. at 295 mu EiZ" ,=660

As far as is known, this compound is not described in the literature.

EXAMPLE IlI Preparation of 3-methoxy-l1,8,18-epoxy-A -estratriene-l7 8-ol and methanol, slightly soluble in isopropylether and in-' soluble in water. p

LR. spectrum (chloroform): Presence of CH COO at 1725 cmr? and of strong OH bands. The RMN spectrum confirmed the structure.

As far as is known, this compound is not described in the literature.

Step B: 3-methoxy-11p,18-epoxy-A -estratriene 17B,l8-diol.--A mixture of 730 mg. of 3-methoxy-18-hydroxyimino-1718-acetoxy-A -estratriene-11B 01, 7.3 cc. of 2 N hydrochloric acid, 7.3 cc. of acetone and 3.65 cc. of acetic acid was stirred for 22 hours at room temperature and the reaction mixture was added to ice water and stirred forl hour. The mixture was vacuum filtered and the precipitate was washed with water and dried under reduced pressure to obtain 455 mg. of 3-methoxy-11B,18-epoxy- A '3 -estratriene-1713-18 diol melting at 207-210 C. The cream crystals were soluble in pyridine, slightly soluble in chloroform and insoluble in water. i

LR. spectrum (chloroform): Absence of acetate and presence of OH at 3573 and 3470 cmr' As far as is known, this compound is'not described in the literature.

Step C: 3-methoxy-A estratriene 115,175,18- triol.A mixture of 440 mg. of 3-methoxy-11fl,18-epoxy- A -estratriene-17B,l8-diol, 22 cc. of tetrahydrofuran and 880 mg. of lithium aluminum hydride was refluxed for 30 hours and then excess hydride was destroyed by the addition of tetrahydrofuran containing 10% water. The

LR. spectrum (chloroform): Presence of OH at 3600 cm: and of aromatic at 1609, 1577 and 1497 cmr 'As far as is known, this compound is not described in the literature. I

The synthesis was continued as in steps E to J of Ex ample I to obtain 11fl,18-epoxy-17a-ethynyl-A --estradiene-l7 3-ol-3-one.

PHARMACOLOGICAL STUDY (A) Exogenic anti-androgenic activity The exogenic anti-androgenic activity was determined against testosterone propionate in castrated male rats in the Lerner method described by Dorfman in Methods in Hormone Research, vol. II, p. 320. Young male rats about 4 weeks old were castrated and treatment was started the day after the castration and was continued for 7 days. On the eighth day, the animals were killed and the rele vant organs, namely prostate, seminal vesicules and levator ani, were recovered. 11,8,18-epoxy-17a-ethynyl-A -estradiene-l7B-ol-3-one and testosterone propionate were used in sesame oil containing 5% benzylic alcohol and they were administered separately subcutaneously, the epoxy compound being administered at 1 mg. per rat and per day and testosterone propionate at 50 per rat and per day. One group of rats serving as the control received only the solvent, one group received 50 of testosterone propionate, one group received 1 mg. of the test compound and 1 group received 1 mg. of the test product and 50 of testosterane propionate. The results were reported in mixture was filtered and the filtrate was evaporated to dry- Table I.

TABLE I Fresh Seminal Lavator (mi vesicules Prostate Group Dally dose in mg. in mg. in mg.

Controls 0 24. 90 7. 6 11. 8 Testosterone proplonate 507. 42. 94. 2 109. 7 Test product. 1 mg 24. 90 7. 6 16. 7 Test product plus testo- 1 mg. plus 507. .29. 90(29%) 30. 3(64%) 55. 4(-50%) sterone propionate.

ness. The residue was subjected to chromatography on In a second test, the test product was administered silica and elution wih a 1:1 mixture of choroform-aceunder the same conditions at a dose of 0.4 mg. and the retone to obtain 280 mg. of 3-methoxy-A -estratrienesults are reported in Table II.

Test Compound plus testol'ng 14. 00 17. 6 13. 9 0.4 mg. plus 607 22. 20(6l%) 47. 40-15%) 65. 7(39%) steroue propionate.

llfl,l7fl,l8-triol melting at 162 C. and then 171 C. The colorless solid was slightly soluble in the usual organic solvents and insoluble in water.

LR. spectrum (Nujol): Presence of 0H at 3175 cm.- and of aromatic at 1604, 1572 and 1498 cmr As far as is known, this compound is not described in the literature.

Step D: 3-methoxy-11B,18-epoxy-A -estratriene- 17.-ol.20 mg. of p-toluene sulfonic acid were added to a suspension of 100 mg. of 3-methoxy-A -estratriene- 1 1B-17B,18-triol in 10 cc. of benzene and the mixture was refluxed for 7 hours. After cooling, the reaction mixture was neutralized with triethylamine addition and was added to water. The mixture was extracted three times with benzene and the combined benzene phases where washed with water, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 0.100 g. of raw product. The latter was purified by chromatography on silica gel and elution with an 8:2 mixture of chloroformacetone to obtain 30 mg. of 3-methoxy-1lfi,l8-epoxy- A -estratriene-17fl-ol melting at 170 C. The colorless solid was soluble in chloroform and insoluble in water.

The results show that the compound of the invention exercises a clear anti-androgenic activity at a dose of 0.4 mg. against a dose of 50 of testosterone propionate.

Various modifications of the compositions and method of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is intended to be limited only as defined in wherein R is selected from the group consisting of hydrogen and ethynyl and R is selected from the group consisting of hydrogen, acyl of an organic carboxylic acid 3. A compoundof claim 1 which is 1113,18-epoxyd7B- acetoxy-Afi-estradiene-3-one.

4. A compound of claim 1 which is 11fl,18v-epoxy- A estradiene-17B-ol-3-one.

5. A process for the preparation of the compound of claim 2 comprising reacting 3-methoxy-A J -estratriene-l 15,17/3-diol with acetic acid anhydride to selectively acetylate the 17-position, reacting the resulting 3- methoxy-l7fl-acetoxy-A -estratriene-1 113-01 with ni trous acid to form 3-methoxy-llfi-nitrosoxy flfl-acetoxya A -estratriene, irradiating the latter in the presence of iodine to form B-methoxy-17/3-acetoxy-iodo-A 2 estratriene-llp-ol, reacting the latter with a strong base to form 3 methoxy 115,18 epoxy-A -estratriene- 175-01, reacting the latter with lithium in liquid ammonia in the persence of an alcohol to form 3-methoxy-11B,18- epoxy-A -estradiene-flp-ol, reacting'the latter with a ketalization agent in an acid media to form the 3-ketal of 1l3,1 8-epoxy-A -estrene-17B-ol-3-one, oxidizing the latter by the Oppenauer reaction with aluminum lower alcoholate in the presence of a hydrogen acceptor to form the 3-ketal of 11B,l8-epoxy-A -estrene-3,l7 dione, reacting the latter with an alkali metal acetylide and then hydrolyzing the product with a weak acid to obtain 11B,18-epoxy-17a-ethynyl-A -estrene-17B-ol-3 one and reacting the latter with bromine in the presence of an organic tertiary base to form 11,3,l8-epoxy-17-a-ethynyl- A' -estradiene-17,8-ol-3-one.

6. A process for the preparation of the compound of claim 4 comprising reacting 3-methoxy-A -estradienelIBJTIB-diol ,with vacetic .acid .anhydrideto ,selec.-. tively acetylate the 17 position, reacting the resulting 3- methoxy:17,8-acetoXy-A -estratriene-1lfl-ol with nitrous l acid to form S-methoXy-I1B-nitrosoxy-l7fl-acetoxyn v -estratriene, irradiating the. latter in the presence of iodine tov form 3-methoxy 1718 acetoxy 18 r iodo- A -estratriene-llfl-ol, reacting the latter with a strong. base to form 3-methoxy.-,11p,18 epoxy-A d estratriene-17 3-ol, reacting the latter with lithium in liquid ammonia in the presence of an alcohol to form 3- the latter with a weak acid to form 11,6,18-epoxy-A- estrene-l7p-ol-3-one and reacting the latter with bromine in the presence of an organic tertiary base to form 11,8,18- epoxy-AF-flestradiene-l7p-ol-3 one. 1 4 v 1 7. A process forthepreparation of 3-methoxy-1 15,18- epoxy- A -estratriene-Ufl-ol comprising subjecting 3- methoxy-l lfl-n'itrosoxy-17B-acetoxy-A D-estratriene to photolysis to form S-methoxy 17/3 acetoxy-lS-hydrdxy imino-n f m-estratriene-11 8-01, reacting the latter with an acid agent to form 3-n1ethoxy-11 3,18-epoxy-A estratriene-l718,18-diol, reacting the latter witha reducing agent to obtain 3-meth0xy-A -estratriene 11B,- 1 7;8,18- triol reacting the latter with acid agent to obtain 3-methoxy-11,8,lg epoxy-Al -estratriene- -01.

References' Cited 7 v UNITED STATES PATENTS] v 3,423,404 1/1969 Klimstra 260-23955 HEN-RY A. FRENCH, Primary mana er I US. Cl. X-R. 

